bims-stacyt 2022-07-03 papers

Arch Pharm Res. 2022 Jun;45(6): 401-416

Crosstalk between angiogenesis and immune regulation in the tumor microenvironment.

Hei Jung Kim, Young Rae Ji, You Mie Lee.

Cancer creates a complex tumor microenvironment (TME) composed of immune cells, stromal cells, blood vessels, and various other cellular and extracellular elements. It is essential for the development of anti-cancer combination therapies to understand and overcome this high heterogeneity and complexity as well as the dynamic interactions between them within the TME. Recent treatment strategies incorporating immune-checkpoint inhibitors and anti-angiogenic agents have brought many changes and advances in clinical cancer treatment. However, there are still challenges for immune suppressive tumors, which are characterized by a lack of T cell infiltration and treatment resistance. In this review, we will investigate the crosstalk between immunity and angiogenesis in the TME. In addition, we will look at strategies designed to enhance anti-cancer immunity, to convert "immune suppressive tumors" into "immune activating tumors," and the mechanisms by which these strategies enhance effector immune cell infiltration.

Keywords: Angiogenesis; Immune suppressive tumor; Treg cells; Tumor microenvironment; Tumor-associated macrophage

DOI: https://doi.org/10.1007/s12272-022-01389-z

Front Oncol. 2022 ;12 816504

Therapeutic Targeting of Tumor Cells and Tumor Immune Microenvironment Vulnerabilities.

Balaraman Kalyanaraman, Gang Cheng, Micael Hardy.

Therapeutic targeting of tumor vulnerabilities is emerging as a key area of research. This review is focused on exploiting the vulnerabilities of tumor cells and the immune cells in the tumor immune microenvironment (TIME), including tumor hypoxia, tumor acidity, the bidirectional proton-coupled monocarboxylate transporters (MCTs) of lactate, mitochondrial oxidative phosphorylation (OXPHOS), and redox enzymes in the tricarboxylic acid cycle. Cancer cells use glucose for energy even under normoxic conditions. Although cancer cells predominantly rely on glycolysis, many have fully functional mitochondria, suggesting that mitochondria are a vulnerable target organelle in cancer cells. Thus, one key distinction between cancer and normal cell metabolism is metabolic reprogramming. Mitochondria-targeted small molecule inhibitors of OXPHOS inhibit tumor proliferation and growth. Another hallmark of cancer is extracellular acidification due lactate accumulation. Emerging results show that lactate acts as a fuel for mitochondrial metabolism and supports tumor proliferation and growth. Metabolic reprogramming occurs in glycolysis-deficient tumor phenotypes and in kinase-targeted, drug-resistant cancers overexpressing OXPHOS genes. Glycolytic cancer cells located away from the vasculature overexpress MCT4 transporter to prevent overacidification by exporting lactate, and the oxidative cancer cells located near the vasculature express MCT1 transporter to provide energy through incorporation of lactate into the tricarboxylic acid cycle. MCTs are, therefore, a vulnerable target in cancer metabolism. MCT inhibitors exert synthetic lethality in combination with metformin, a weak inhibitor of OXPHOS, in cancer cells. Simultaneously targeting multiple vulnerabilities within mitochondria shows synergistic antiproliferative and antitumor effects. Developing tumor-selective, small molecule inhibitors of OXPHOS with a high therapeutic index is critical to fully exploiting the mitochondrial vulnerabilities. We and others developed small-molecule inhibitors containing triphenylphosphonium cation that potently inhibit OXPHOS in tumor cells and tissues. Factors affecting tumor cell vulnerabilities also impact immune cells in the TIME. Glycolytic tumor cells supply lactate to the tumor-suppressing regulatory T cells overexpressing MCTs. Therapeutic opportunities for targeting vulnerabilities in tumor cells and the TIME, as well as the implications on cancer health disparities and cancer treatment, are addressed.

Keywords: Mitochondrial drugs; metabolic reprogramming; monocarboxylate transporters; oxidative phosphorylation (OXPHOS); tumor microenvironment

DOI: https://doi.org/10.3389/fonc.2022.816504

Int Immunopharmacol. 2022 Jun 25. pii: S1567-5769(22)00452-0. [Epub ahead of print]110 108968

Normalization of tumor vasculature: A potential strategy to increase the efficiency of immune checkpoint blockades in cancers.

Yu Shi, Yang Li, Baokang Wu, Chongli Zhong, Qi Lang, Zhiyun Liang, Yizhou Zhang, Chao Lv, Shushen Han, Yang Yu, Feng Xu, Yu Tian.

Immune checkpoint inhibitors (ICIs) eliminate tumor cells by reactivating CD8 + T cells using the cytotoxic effects of the immune system. However, in this process, tumor angiogenic factors and abnormal formation of tumor blood vessels are not conducive to the treatment of ICIs. In the tumor microenvironment (TME), proangiogenic factors prevent dendritic cell maturation, reduce T cell infiltration, and recruit inhibitory immune cells such as regulatory T (Treg) cells. Abnormal tumor blood vessels also prevent immune cells and chemotherapy drugs from reaching the target effectively and lead to poor perfusion and severe hypoxia of the tumor. Treatment with antiangiogenic inhibitors can block the transmission of abnormal angiogenesis signals and promote the normalization of tumor vasculature. Therefore, the combination of antiangiogenic inhibitors and ICIs is used in clinical therapy. Combination therapy has been proven theoretically feasible in preclinical trials, and many clinical trials have been completed to confirm its safety and efficacy.

Keywords: Angiogenic factor; Cancer treatment; Immune checkpoint inhibitors; Immunotherapy; Tumor vasculature

DOI: https://doi.org/10.1016/j.intimp.2022.108968

Chronic Dis Transl Med. 2022 Jun;8(2): 124-133

Recombinant human erythropoietin accelerated the proliferation of non-small cell lung cancer cell lines and reduced the expression of VEGF, HIF-1α, and PD-L1 under a simulated hypoxic environment in vitro.

Yajing Zhang, Yangchun Feng, Xiaojie Sun.

Background: As erythropoietin (EPO) has been used to treat anemia in cancer patients, negative controversy has continued. Unfortunately, its effects on non-small-cell lung carcinoma (NSCLC) cell lines are uncertain and the phenomenon of inducing immune escape of tumor cells remains to be explored. This study aimed to provide an important basis for the application of exogenous EPO in the treatment of tumor-associated anemia.
Methods: Cells were cultured in 1% O2, 5% CO2, and 94% N2 to simulate a hypoxic environment of the tumor. A549 cell line (lower expression EPOR) and NCI-H838 cell line (higher expression EPOR) were treated with 2 and 8 U/ml recombinant human EPO (rhEPO). CCK-8 method was used to determine the logarithmic growth phase of the cells and to detect cell proliferation. The expression levels of VEGF, HIF-1α, and PD-L1 were determined by western blot. One-way ANOVA was used for statistical analysis between groups, with p < 0.05 indicating a significant difference.
Results: Hypoxia itself could decrease the survival rate of NSCLC cells. Under the hypoxic condition, rhEPO induced tumor cells proliferation, especially in the NCI-H838 cell line, where 2 U/ml rhEPO increased the total number of surviving cells (Hypoxia + rhEPO 2 U/ml vs. Hypoxia, p < 0.05). Western blot analysis showed that hypoxia upregulated the expression of VEGF, HIF-1α, and PD-L1 in NSCLC cell lines (Normoxia vs. Hypoxia, p < 0.05), but may not be dependent on the expression levels of EPOR. RhEPO decreased the expression levels of VEGF and HIF-1α. In the A549 cell line, it depended on the concentration of rhEPO and was particularly obvious in HIF-1α (Hypoxia vs. Hypoxia + rhEPO 2 U/ml vs. Hypoxia + rhEPO 8 U/ml, p < 0.05). A low concentration of rhEPO may not reduce VEGF expression. In the NCI-H838 cell line, the effect of rhEPO on VEGF was more obvious, but it may be independent of rhEPO concentrations. The downregulation of PD-L1 expression by rhEPO was only presented in the A549 cell line and required higher rhEPO concentrations (Hypoxia + rhEPO 8 U/ml vs. Hypoxia&Hypoxia + rhEPO 2 U/ml, p < 0.05).
Conclusion: The effect of prolonged high concentrations of rhEPO under hypoxic conditions resulted in accelerated cells proliferation of non-small-cell lung cancer and was independent of EPOR expression levels on the cell lines surface. Hypoxia resulted in increased expression of VEGF, HIF-1α, and PD-L1 on the NSCLC cell lines. Under normoxic conditions, rhEPO did not affect the expression of VEGF, HIF-1α, and PD-L1; but under hypoxic conditions, the application of rhEPO reduced the expression of VEGF, HIF-1α, and PD-L1, producing an impact on the biological behavior of tumor cells.

Keywords: cell proliferation; hypoxia; hypoxia‐inducible factor 1; non‐small cell lung cancer; vascular endothelial growth factor

DOI: https://doi.org/10.1002/cdt3.12

Compr Psychoneuroendocrinol. 2021 Aug;7 100073

Macrophage-derived secretome is sufficient to confer olanzapine-mediated insulin resistance in human adipocytes.

Priya Dipta, Assel Sarsenbayeva, Miriam Shmuel, Francesca Forno, Jan W Eriksson, Maria J Pereira, Xesús M Abalo, Martin Wabitsch, Morten Thaysen-Andersen, Boaz Tirosh.

Objective: Olanzapine and Aripiprazole are widely used second-generation antipsychotic drugs. Olanzapine, more than Aripiprazole, leads to considerable metabolic side effects including obesity and diabetes. While the underlying mechanisms are not fully understood, these side effects are likely associated with mild inflammation in the metabolic organs. An in vitro model that accurately recapitulates the metabolic impact of olanzapine and aripiprazole should be useful to elucidate the underlying mechanisms.
Methods: We established co-cultures of matured adipocytes derived from the human SGBS cell line and the THP-1 human monocytic cell-derived or primary macrophages to explore the effects of both drugs on the response to insulin.
Results: Olanzapine, but not aripiprazole induced insulin resistance in SGBS adipocytes only when co-cultured with THP-1 or primary macrophages, polarized either into M0, M1 or M2. Noteworthy, M2 macrophages induced olanzapine-dependent insulin resistance in the absence of induction of pro-inflammatory cytokines. Insulin resistance by olanzapine was stronger than induced by high concentration of pro-inflammatory cytokines even in combinations, suggesting the contribution of factors other than the classical inflammatory cytokines to promote insulin resistance in adipocytes by olanzapine.
Conclusion: Macrophage/adipocyte co-cultures recapitulate the features of olanzapine-induced insulin resistance and implicate the existence of yet unknown factors in mediating this effect.

Keywords: Adipocytes; Antipsychotics; Inflammation; Insulin resistance; Macrophages

DOI: https://doi.org/10.1016/j.cpnec.2021.100073

J Cell Sci. 2022 Jul 01. pii: jcs.259090. [Epub ahead of print]

Redox-dependent AMPK inactivation disrupts metabolic adaptation to glucose starvation in xCT-overexpressing cancer cells.

Younghwan Lee, Yoko Itahana, Choon Chen Ong, Koji Itahana.

Accelerated aerobic glycolysis is a distinctive metabolic property of cancer cells that confers dependency on glucose for survival. However, the therapeutic strategies targeting this vulnerability are still inefficient and have unacceptable side effects in clinical trials. Therefore, developing biomarkers to predict therapeutic efficacy would be essential to improve the selective targeting of cancer cells. Here, we found that the cell lines sensitive to glucose deprivation have high expression of cystine/glutamate antiporter xCT. We found that cystine uptake and glutamate export through xCT contributed to rapid NADPH depletion under glucose deprivation. This collapse of the redox system oxidized and inactivated AMPK, a major regulator of metabolic adaptation, resulting in a metabolic catastrophe and cell death. While this phenomenon was prevented by pharmacological or genetic inhibition of xCT, overexpression of xCT sensitized resistant cancer cells to glucose deprivation. Taken together, these findings suggest a novel cross-talk between AMPK and xCT for the metabolism and signal transduction and reveal a metabolic vulnerability in xCT-high expressing cancer cells to glucose deprivation.

Keywords: AMPK; Cystine; Glucose starvation; NADPH; SLC7A11; xCT

DOI: https://doi.org/10.1242/jcs.259090